Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg EffectReportar como inadecuado




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Background

The unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However -aerobic glycolysis- generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage.

Methods-Findings

We carried out a screen for loss of genetic elements in pancreatic tumor cells that accelerated their growth as tumors, and identified mitochondrial ribosomal protein L28 MRPL28. Knockdown of MRPL28 in these cells decreased mitochondrial activity, and increased glycolysis, but paradoxically, decreased cellular growth in vitro. Following Warburg-s observations, this mutation causes decreased mitochondrial function, compensatory increase in glycolysis and accelerated growth in vivo. Likewise, knockdown of either mitochondrial ribosomal protein L12 MRPL12 or cytochrome oxidase had a similar effect. Conversely, expression of the mitochondrial uncoupling protein 1 UCP1 increased oxygen consumption and decreased tumor growth. Finally, treatment of tumor bearing animals with dichloroacetate DCA increased pyruvate consumption in the mitochondria, increased total oxygen consumption, increased tumor hypoxia and slowed tumor growth.

Conclusions

We interpret these findings to show that non-oncogenic genetic changes that alter mitochondrial metabolism can regulate tumor growth through modulation of the consumption of oxygen, which appears to be a rate limiting substrate for tumor proliferation.



Autor: Yijun Chen, Rob Cairns, Ioanna Papandreou, Albert Koong , Nicholas C. Denko

Fuente: http://plos.srce.hr/



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